KR20080066746A - Process for production of biphenyl derivatives - Google Patents

Abstract

A process for the production of biphenyl derivatives represented by the general formula (1), which is characterized by comprising reacting the chlorine atom of a benzene derivative represented by the general formula (2) with metallic magnesium to form a Grignard reagent and coupling two molecules of the Grignard reagent with each other in the presence of a catalyst and which is excellent in industrial productivity by virtue of its using inexpensive and easily available raw materials. (1) (2) (wherein A's are at least one member selected from between trifluoromethyl and fluoro; and n is an integer of 1 to 4)

Description

Production method of biphenyl derivative {PROCESS FOR PRODUCTION OF BIPHENYL DERIVATIVES}

The present invention relates to a method for producing a biphenyl derivative, and more particularly to a method for producing an industrially superior biphenyl derivative.

Biphenyl derivatives are compounds widely used in the field of organic chemistry and polymer chemistry, and are useful in a wide range of fields for industrial use such as fine chemicals, pharmaceutical raw materials, resins and plastic raw materials, electronic information materials, and optical materials.

As a method for producing a biphenyl derivative, it is known to use an aromatic halide as a starting substrate. PTL 1 proposes a method of reacting an aromatic bromide with a Grignard reagent of an aromatic chloride in the presence of a nickel catalyst. On the other hand, Non-Patent Documents 1 and 2 convert an aromatic iodide or an aromatic bromide into magnesium to convert it into a Grignard reagent, and then couple Grignard reagents together in the presence of an oxidant using an iron (III) chloride catalyst. The manufacturing method to ring is proposed.

However, in the method described in Patent Literature 1, when the substrate to be reacted with the Grignard reagent became an aromatic chloride, the yield of the biphenyl derivative was low and could not be industrially applied. In addition, although the manufacturing method described in Nonpatent Documents 1 and 2 has high reactivity as a starting substrate, expensive biphenyl derivatives produced due to the use of expensive aromatic iodide or aromatic bromide have also become expensive.

Patent Document 1: Japanese Patent Application Laid-Open No. 63-295520 (Examples 1, 2, 3, 4)

[Non-Patent Document 1] Organic Letters, Vol. 7, No. 3 (2005), 491-493

[Non-Patent Document 2] Organic Letters, Vol. 7, No. 10 (2005), 1943-1946

An object of the present invention is to provide a method for producing a biphenyl derivative which is industrially excellent in productivity by using a raw material which is inexpensive and readily available.

A method for producing a biphenyl derivative of the present invention which achieves the above object is a method for producing a biphenyl derivative represented by the following general formula (1), wherein the chlorine atom of the benzene derivative represented by the following general formula (2) is magnesium metal React with the Grignard reagent, and the Grignard reagents are coupled to each other in the presence of a catalyst.

(Wherein A represents at least one selected from a trifluoromethyl group and fluorine, and n is an integer of 1 to 4).

(Wherein A represents at least one selected from a trifluoromethyl group and fluorine, and n is an integer of 1 to 4).

The method for producing a biphenyl derivative of the present invention can produce a Grignard reagent as an intermediate at low cost in terms of using an inexpensive aromatic chloride as a starting substrate, and efficiently conducts a coupling reaction between these Grignard reagents efficiently. Can be produced under high productivity.

Below, the detail of this invention is described.

The manufacturing method of the biphenyl derivative of this invention uses the benzene derivative represented by following General formula (2) as a starting substrate.

(Wherein A represents at least one selected from a trifluoromethyl group and fluorine, and n is an integer of 1 to 4).

In said formula (2), n is an integer of 1-4, Preferably it is 1. This is because a cheaper starting substrate can be used when n is 1, and furthermore, the reaction proceeds more efficiently since there is little effect of inhibiting steric reaction by a substituent in the present reaction.

Specific examples of starting substrates include o-chlorobenzotrifluoride, m-chlorobenzotrifluoride, p-chlorobenzotrifluoride, di (trifluoromethyl) -chlorobenzene, tri (trifluoromethyl) -chlorobenzene , Tetra (trifluoromethyl) -chlorobenzene, o-chloro-fluorobenzene, m-chloro-fluorobenzene, p-chloro-fluorobenzene, chloro-difluorobenzene, chloro-trifluorobenzene, Chloro-tetrafluorobenzene and the like, among which preferred are o-chlorobenzotrifluoride, m-chlorobenzotrifluoride, p-chlorobenzotrifluoride, o-chloro-fluorobenzene, m- Chloro-fluorobenzene, p-chloro-fluorobenzene.

In the present invention, the chlorine atom of the benzene derivative of formula (2) is reacted with magnesium metal to be converted into a Grignard reagent. The conversion reaction to the Grignard reagent is not particularly limited, and a known conversion reaction can be used.

Although magnesium metal is not specifically limited, It is preferable to use a powder form.

The reaction converted to Grignard reagent is carried out by a dehydrated system. Preference is given to using dehydrated solvents or adding inexpensive Grignard reagents to remove the water.

In addition, in order to increase the reactivity by taking a surface oxide film of magnesium metal, iodine, bromine or an inexpensive compound containing these may be added. As an example of such a compound, methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, etc. are mentioned preferably.

The catalyst used in the coupling reaction between Grignard reagents in the production method of the present invention may preferably be Fe, Ag, Cu, Co, Zn, Ni, Pd metal or a compound thereof. Chloride, bromide, iodide, fluoride, acetate, acetylacetonato salts, carbonates, hydroxides and nitrates are preferably used. Among them, ferrous chloride (II), ferric chloride (III), ferrous bromide and ferric bromide are preferred.

In addition, it is preferable to use 0.01 mol%-20 mol% with respect to 1 mol of starting substrates, and, as for the usage-amount of a catalyst, 0.05 mol%-10 mol% are more preferable. By using the amount of the catalyst in the above range, the coupling reaction can be performed efficiently and economically.

It is preferable that the manufacturing method of this invention performs a coupling reaction in the coexistence of an oxidizing agent. This is because, in the presence of an oxidant, the catalyst reduced by the coupling reaction is easily oxidized and regenerated, so that the turnover number of the catalyst is improved and the reaction yield is improved.

The oxidizing agent is not particularly limited as long as the metal can be oxidized, but halogenated aliphatic hydrocarbons are preferable from the viewpoints of handling and separation from the product, and more preferably halogenated aliphatic hydrocarbons having 1 to 5 carbon atoms. Specifically, chloromethane, dichloromethane, chloroform, carbon tetrachloride, bromomethane, dibromomethane, tribromomethane, tetrabromomethane, chloroethane, dichloroethane, trichloroethane, tetrachloroethane, tetrachloro Ethylene, pentachloroethane, hexachloroethane, bromoethane, dibromoethane, tribromoethane, tetrabromoethane, chloropropane, dichloropropane, trichloropropane, chlorobutane, dichlorobutane, chloropentane, dichloropentane , Bromopropane, dibromopropane, tribromopropane, bromochloromethane, bromochloroethane and the like. Among them, preferred are chloromethane, dichloromethane, chloroethane, dichloroethane, dichloropropane, bromomethane, dibromomethane, bromoethane, dibromoethane, dibromopropane, and more preferably dichloropropane. .

Moreover, it is preferable to use 0.1 mol times-5 mol times with respect to 1 mol of starting substrates, and, as for the usage-amount of an oxidizing agent, 0.2 mol times-3 mol times are more preferable. When the amount is less than 0.1 mole, the effect of catalyst regeneration by the oxidant is less. When the molar amount is more than 5 mole, the unreacted oxidant remains, and the load is applied by the isolation and purification of the target, which is inefficient.

Any solvent may be arbitrarily selected as long as the solvent used in the production method of the present invention can efficiently proceed with reaction. Preferably, an ether solvent which is easy to generate Grignard reagent is preferable. Specific examples of the solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dioxane, 1,4 -Dioxane, cyclopropyl methyl ether, methyl-tert-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, benzene, toluene, xylene and the like. Among them, preferred are diethyl ether, diisopropyl ether, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, cyclopropylmethyl ether, and methyl-tert-butyl ether.

The amount of the solvent may be any amount depending on the solubility of the benzene derivative, the Grignard reagent and the product represented by the formula (2), the slurry concentration or the property of the reaction solution, but is preferably represented by the formula (2). It is 0.5-100 mole times with respect to the benzene derivative shown. If it is less than 0.5 mole times, the yield of Grignard reagent is low, and if it exceeds 100 mole times, productivity is bad and becomes an uneconomical process.

In the manufacturing method of this invention, 45-100 degreeC is preferable and, as for the reaction temperature of a coupling reaction, 55-70 degreeC is more preferable. If the reaction temperature is lower than 45 ° C., the reaction hardly proceeds. For example, even if the reaction proceeds, the reaction may be stopped halfway. If the reaction temperature exceeds 100 ° C., the Grignard reagent may be decomposed before the reaction. Not.

In the manufacturing method of this invention, a biphenyl derivative represented by following General formula (3) is produced | generated by the biphenyl derivative represented by following General formula (1) at the time of a coupling reaction, and it is biphenyl. A composition containing a derivative is obtained.

(Wherein A represents at least one selected from a trifluoromethyl group and fluorine, and n is an integer of 1 to 4).

(Wherein A represents at least one selected from a trifluoromethyl group and fluorine, X represents a halogen atom, n is an integer of 1 to 4, a and b are integers, and the sum of a and b is 1 to 1) 8)

It is preferable that the content of the halogenated biphenyl derivative represented by said Formula (3) is 20 weight% or less, and, as for the composition containing the biphenyl derivative obtained by the manufacturing method of this invention, 0.01 weight%-20 weight% are more preferable. . This is because when the halogenated biphenyl derivative exceeds 20% by weight, it is used as a raw material for fine chemicals, medicinal pesticide raw materials, resin / plastic raw materials, electronic information materials, optical materials, etc., resulting in deterioration of the final product. That is, quality problems, such as the fall of the purity of a final product, coloring, a fall of intensity | strength, and the fall of an optical characteristic, generate | occur | produce, and are not preferable.

Therefore, when the content of the halogenated biphenyl derivative by-produced in the production method of the present invention is large, separation and removal of the halogenated biphenyl derivative from the coupling reaction liquid obtained is carried out to reduce the content as much as possible to isolate the desired biphenyl derivative. It is desirable to. The isolation method is preferably a distillation purification method, a crystallization method, an extraction method, a column separation with silica, a pseudo moving bottom adsorptive separation method, or the like, and any isolation method may be used, but distillation purification is more preferable. In addition, it is also possible to further refine the purity by combining a plurality of methods of these isolation methods.

In the present invention, since active magnesium or the like may remain in the reaction solution, water or acidic water is added to the reaction solution to remove the magnesium salt produced by the reaction with an aqueous phase, followed by obtaining an oil phase. Preference is given to a method of isolating the biphenyl derivative from (phase). For example, the distillation purification method may be any one of distillation, rectification, vacuum distillation and atmospheric distillation, but preferably vacuum distillation is used. In distillation purification, since the halogenated biphenyl derivative is higher boiling point than the desired biphenyl derivative, distillation operation such as distilling the biphenyl derivative and leaving the halogenated biphenyl derivative as distilled as possible without leaving distillation as possible is necessary.

In the production method of the present invention, the halogenated biphenyl derivative content in the biphenyl derivative obtained by any of the isolation methods is preferably 0.01% by weight to 20% by weight, more preferably 0.01% by weight to 5% by weight. good. By setting the halogenated biphenyl derivative content within the above range, the quality of purity, coloring, strength, optical properties and the like of the final product using the biphenyl derivative as a raw material can be maintained.

The biphenyl derivative obtained by the manufacturing method of this invention can be converted into various compounds in the field of various fields, and it is significant that it is obtained industrially cheaply and efficiently.

Hereinafter, although an Example demonstrates this invention still in detail, this invention is not limited to this.

(Example)

The maker grades of the reagents used in the following examples and comparative examples are all equivalent to the first level or higher, unless otherwise noted.

Example 1

143.6 g of tetrahydrofuran (1.99 mol; manufactured by nacalai tesque) and 16.1 g of magnesium powder (0.664 mol; manufactured by Chuokosan) were charged into a reactor with a thermometer, and the inside of the system was stirred with nitrogen substitution. 2 g (0.017 mol; made by Tokyo Kasei Co., Ltd.) of tert- butylmagnesium chloride was added, and the water in system was removed. Next, 10 g of o-chlorobenzotrifluoride (0.0554 mol; manufactured by MITENI) was added thereto, and then 2 g of ethyl bromide (0.018 mol; manufactured by nacalai tesque) was added thereto. It stirred for a while and confirmed that exotherm occurred. Next, 90 g (0.499 mol) of o-chlorobenzo trifluorides was dripped, maintaining at the reaction liquid temperature of 35-50 degreeC. After completion of dropping, the mixture was aged with stirring at 45 ° C for 3 hours. The yield of Grignard reagent was 91%.

Next, 65 g (0.664 mol; manufactured by nacalai tesque) of 1,2-dichloroethane were added to a solution obtained by adding 3 g (0.04 mol) of tetrahydrofuran to 2.70 g (0.0166 mol; manufactured by Wako Pure Chemical Industries, Ltd.) of iron (III) chloride. A catalyst containing solution was prepared. This was dripped at the said Grignard reagent solution, maintaining the reaction liquid temperature at 45-60 degreeC, and the coupling reaction was performed. After completion of the dropwise addition, the reaction was carried out at 65 ° C for 3 hours. After the reaction was completed, the mixture was cooled, the reaction solution was developed in water, the oil layer was extracted with diethyl ether (manufactured by nacalai tesque, Ltd.), and acetophenone (manufactured by nacalai tesque, Ltd.) as an internal standard was added thereto. And a gas chromatography method (column: GL Science Co., Ltd .: inner cap 1, length 60 m, diameter 0.25 mm, film thickness 0.40 m). The yield of 2,2'-trifluoromethylbiphenyl relative to o-chlorobenzotrifluoride was 69%. In addition, the by-product chloro2,2'- trifluoromethylbiphenyl was 11 weight% with respect to 2,2'-trifluoromethylbiphenyl.

Example 2

In Example 1, the reaction was carried out in the same manner as in Example 1 except that the catalyst was changed from iron (III) chloride to 5.86 g (0.0166 mol; manufactured by Wako Pure Chemical Industries, Ltd.) as iron (III) acetylacetonato. The yield of 2,2'-trifluoromethylbiphenyl relative to o-chlorobenzotrifluoride was 48%. In addition, the by-produced chloro2,2'-trifluoromethylbiphenyl was 6.7 wt% with respect to 2,2'-trifluoromethylbiphenyl.

Example 3

In Example 1, the reaction was carried out in the same manner as in Example 1 except that 1,2-dichloroethane was changed to 124.7 g (0.664 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 1,2-dibromoethane. The yield of 2,2'-trifluoromethylbiphenyl relative to o-chlorobenzotrifluoride was 38%. In addition, the by-product chloro2,2'-trifluoromethylbiphenyl was 29 weight% with respect to 2,2'-trifluoromethylbiphenyl.

Example 4

In Example 1, reaction was carried out similarly to Example 1 except having changed the 1,2-dichloroethane to 75.0g (0.664mol; Wako Pure Chemical Industries, Ltd.) of 1,2-dichloropropane. The yield of 2,2'-trifluoromethylbiphenyl relative to o-chlorobenzotrifluoride was 72%. In addition, the by-product chloro2,2'-trifluoromethylbiphenyl was 8.5 weight% with respect to 2,2'-trifluoromethylbiphenyl.

Example 5

In Example 4, 75.0 g (0.664 mol; made by Wako Pure Chemical Co., Ltd.) of 1,2-dichloropropane was added to a solution obtained by adding 3 g (0.04 mol) of tetrahydrofuran to 2.70 g (0.0166 mol; manufactured by Wako Pure Chemical). The reaction was carried out in the same manner as in Example 4 except that the Grignard reagent solution was added dropwise while maintaining the reaction solution temperature at 45 to 60 ° C. to the catalyst-containing solution to which) was added. The yield of 2,2'-trifluoromethylbiphenyl relative to o-chlorobenzotrifluoride was 73%. In addition, the by-product chloro2,2'-trifluoromethylbiphenyl was 1.7 weight% with respect to 2,2'-trifluoromethylbiphenyl.

Example 6

In Example 1, reaction was performed similarly to Example 1 except having changed o-chlorobenzo trifluoride into m-chlorobenzo trifluoride (made by MITENI). The yield of 3,3'-trifluoromethylbiphenyl relative to m-chlorobenzotrifluoride was 41%. In addition, the by-product chloro 3,3'- trifluoromethyl biphenyl was 10.5 weight% with respect to 3,3'- trifluoromethyl biphenyl.

Example 7

In Example 4, 10 g of o-chlorobenzotrifluoride was changed to 7.2 g of p-chlorofluorobenzene (0.0554 mol; manufactured by Wako Pure Chemical), and 90 g of o-chlorobenzotrifluoride was changed to p-chlorofluoro. The reaction was carried out in the same manner as in Example 4, except that 65.2 g of benzene (0.499 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was changed. The yield of 4,4'-difluorobiphenyl relative to p-chlorofluorobenzene was 55%. In addition, the by-product chloro4,4'-difluorobiphenyl was 3.5 weight% with respect to 4,4'-difluorobiphenyl.

Comparative Example 1

143.6 g of tetrahydrofuran (1.99 mol; manufactured by nacalai tesque) and 16.1 g of magnesium powder (0.664 mol; manufactured by Chuokosan) were charged into a reactor with a thermometer, and the inside of the system was stirred with nitrogen substitution. 2 g (0.017 mol; made by Tokyo Kasei Co., Ltd.) of tert- butylmagnesium chloride was added, and the water in system was removed. Next, 10 g of o-chlorobenzotrifluoride (0.0554 mol; manufactured by MITENI) was added thereto, and then 2 g of ethyl bromide (0.018 mol; manufactured by nacalai tesque) was added thereto. It stirred for a while and confirmed that exotherm occurred. Next, 90 g (0.499 mol) of o-chlorobenzo trifluorides was dripped, maintaining at the reaction liquid temperature of 35-50 degreeC. After completion of dropping, the mixture was aged with stirring at 45 ° C for 3 hours. The yield of Grignard reagent was 91.0%.

Next, a solution obtained by dissolving 3.59 g of anhydrous nickel chloride (0.028 mol; manufactured by nacalai tesque) in 30 g of tetrahydrofuran was slowly added to the Grignard reagent solution while maintaining the solution temperature at 40 ° C. Next, 100 g of o-chlorobenzo trifluorides were added dropwise while maintaining the reaction temperature at 60 ° C. After the completion of the reaction, it was analyzed in the same manner as in Example 1 by the gas chromatography method. The yield of 2,2'-trifluoromethylbiphenyl relative to o-chlorobenzotrifluoride was 2%. In addition, the by-product of chloro2,2'-trifluoromethylbiphenyl was not confirmed.

Example 8

100 g of the reaction solution obtained in Example 1 was added to 100 g of an aqueous 3% hydrochloric acid solution contained in a 300 ml aliquot, and mixed well at room temperature for 30 minutes, and allowed to stand for 30 minutes. After standing, liquid-separated and obtained 78.3 g of payments. And this oil phase was monostilled under reduced pressure. After the first distillation cutting, 17.3 g of distillate at 100 to 130 ° C was obtained under the conditions of a vacuum degree of 1.33 kPa. The concentration of 2,2'-trifluoromethylbiphenyl in the obtained distillate was 95.6 wt%, and the concentration of chloro2,2'-trifluoromethylbiphenyl was 3.5 wt%.

Claims (8)

In the manufacturing method of the biphenyl derivative represented by following General formula (1): The chlorine atom of the benzene derivative represented by following General formula (2) is made to react with magnesium metal, and it is converted into the Grignard reagent, Comprising: Process for producing a biphenyl derivative characterized in that the coupling reaction in the presence of a catalyst.

(Wherein A represents one or more selected from trifluoromethyl groups and fluorine, and n is an integer of 1 to 4).

(Wherein A represents one or more selected from trifluoromethyl groups and fluorine, and n is an integer of 1 to 4). The method for producing a biphenyl derivative according to claim 1, wherein the number n of the substituents A in Formula (2) is one. The method for producing a biphenyl derivative according to claim 1 or 2, wherein the catalyst is at least one metal or a compound thereof selected from Fe, Ag, Cu, Co, Zn, Ni, and Pd. The method for producing a biphenyl derivative according to any one of claims 1 to 3, wherein the coupling reaction is performed in the presence of an oxidizing agent. The method of claim 4, wherein the oxidant is a halogenated aliphatic hydrocarbon. The method for producing a biphenyl derivative according to any one of claims 1 to 5, wherein the reaction temperature of the coupling reaction is 45 to 100 ° C. The said biphenyl derivative is distilled and refine | purified, and content of the halogenated biphenyl derivative represented by following General formula (3) is 0.01 weight%-20 weight% in any one of Claims 1-6. The method for producing a biphenyl derivative.

(Wherein A represents one or more selected from trifluoromethyl groups and fluorine, X represents a halogen atom, n is an integer of 1 to 4, a and b are integers, and the sum of a and b is 1 to 1) 8) The composition containing the biphenyl derivative obtained by the manufacturing method in any one of Claims 1-7: Content of the halogenated biphenyl derivative represented by following General formula (3) is 0.01 weight%-20 weight% Biphenyl derivative composition, characterized in that.

(Wherein A represents one or more selected from trifluoromethyl groups and fluorine, X represents a halogen atom, n is an integer of 1 to 4, a and b are integers, and the sum of a and b is 1 to 1) 8)